#244 ‒ The history of the cell, cell therapy, gene therapy, and more | Siddhartha Mukherjee
Episode Stats
Length
1 hour and 40 minutes
Words per Minute
159.32066
Summary
Siddhartha Mukherjee is a cancer researcher and a practicing oncologist. He s an assistant professor of medicine at Columbia University and a staff cancer physician at the Columbia University Hospital. He also happens to be a luminary author, having written four books: The Emperor of All Maladies, The Laws of Medicine, The Gene, and his most recent book, The Song of the Cell, an exploration of medicine and the new human.
Transcript
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Hey, everyone. Welcome to the drive podcast. I'm your host, Peter Atiyah. This podcast,
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my website, and my weekly newsletter all focus on the goal of translating the science of longevity
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at the end of this episode, I'll explain what those benefits are. Or if you want to learn more now,
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head over to peteratiyahmd.com forward slash subscribe. Now, without further delay, here's
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today's episode. My guest this week is Siddhartha Mukherjee. Sid was a previous guest on episode
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number 32, way back, boy, December 2018, I believe. Sid is a cancer researcher and a cancer
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physician, a practicing oncologist. He's an assistant professor of medicine at Columbia University
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and a staff cancer physician at the Columbia University NYU Presbyterian Hospital. He also
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happens to be a luminary author. He's written four books, The Emperor of All Maladies, The Laws of
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Medicine, The Gene, and his most recent book, The Song of the Cell, An Exploration of Medicine
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and the New Human. In my first podcast with Sid, we mostly discussed The Emperor of All Maladies,
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The Biography of Cancer, a book that won him the Pulitzer Prize. In this podcast, we primarily discuss
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his most recent book, The Song of the Cell. This is a book that I just devoured. And I wouldn't have
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thought I could find a book about the history of the cell so interesting. But as you can tell by
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the fact that we're doing this podcast, I clearly did. We talk about so many things that I think to
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sort of try to do it in the intro would do it no justice. But we go everything really from the
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evolutionary drive to go from single cell to multi-cell organisms, all the way up to cell therapy,
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gene therapy, CRISPR, of course, all these things. So we talk a lot about Sid's writing process as well,
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given that he's such a prolific writer, and frankly, some very personal things, including
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his decision to open up about his own depression in his writing. So it's always a pleasure for me
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to sit down and talk with Sid, especially when we can do it like this and record it. So without
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further delay, please enjoy my conversation with Sid Mukherjee.
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Hey, Sid. So great to see you again. It's been a long time since we've seen each other in person.
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The last time we sat down for one of these, of course, it was in person and we didn't have video.
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And now we've got video, but we're in a different time zone. Congratulations on the
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success of your most recent book. For folks listening or viewing, give us a sense of where
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this book fits into the prior work. We talked at great length about one of your books, The Emperor
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of All Maladies, but there was a book that followed that. And then of course, there's this. So maybe put
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this in the context of those books. This is part of a trilogy and possibly a quartet that I'm
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working on broadly called the Life Series. And the attempts of these books is to try to explain
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and understand how we understand life and how we're manipulating life, living things,
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obviously, particularly humans. In an odd way, the place to begin to some extent, the trilogy
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right now. So the first book, The Emperor of All Maladies, the second, The Gene, and now The Song of
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All Maladies, would be to probably start with the gene. Now the gene being the least unit or the
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smallest unit of information. And then realize as you end the gene, that genes which are encoded in
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DNA, the molecule DNA, are lifeless. They don't have any autonomous life. A gene is just a molecule,
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it's a chemical. And it's the cell that brings it to life. And without the cell, there would be
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nothing. All of that code would be useless. I liken the human genome, or any genome, to a score
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of music. But a score is lifeless. There's no music in a score. It's just a code. You need a musician
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to bring it to life. And the cell is that musician. Hence the title of the book, The Song of the Cell.
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The cell brings it to life. So the second book, to some extent, is The Cell. And then the third book,
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bizarrely enough, is the first book. It's sort of like Star Wars, the prequel to the sequel to
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the prequel, where you learn about what happens when cells become aberrant. So that would be one
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way to read the series of books. Start with the gene, move on to the second unit, which is the cell,
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and finally end up with the dysfunctional aberrant cell and what happens to it when its genes go haywire.
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A completely different way would be to read them as they appeared. And the reason behind that is that
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they progressively go downwards. I mean, the first book was, of course, A History of Cancer
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and Cancer Therapy, they progressively go downwards and delve deeper and deeper into mysteries of that
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history, you know, missing pieces. What did we not understand about cancer? Obviously, genes and
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genetics. What did we not understand about cancer in terms of its cell biology when the cancer genome
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atlas was, for instance, completed? And what do we understand now? So they can also be read
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chronologically from the first to the third, you would get a different kind of story. And that's
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what's interesting about it. You can read it by the way. It's possible that my question slash
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statement here is tainted by a bit of recency bias because I read them in order. And of course,
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I've just finished reading The Cell because we decided on a very last minute basis, we were going
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to try to do this podcast. Last minute for the way my podcast works, which is months of preparation.
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So, you know, I was reading the book in the period of the last week and a half, which I enjoyed
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immensely. But here's the thing. I felt more surprised and in awe of the characters in this
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book than the previous books. And that might sound crazy because you'd think, God, decoding the human
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genome, what a Herculean feat. But in many ways, the characters of this story blew my mind even more
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because of the time and the era in which they had to do their science. There were fewer tools at
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their disposal. Does that statement surprise you or how does that resonate with you?
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It's not surprising. It's because the characters in this book are enunciating things that are,
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I think, very fundamental. If you take, for instance, a comparison, if you were to do a historical
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comparison with the history of genetics, in the scientific world, you would start with Mendel,
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Greger Mendel, of course, being the pioneer here. And then there's an enormous period of silence
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that follows Mendel, almost 40 years, in which basically nothing happens. And then, you know,
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his work is picked up by other people, ultimately picked up by folks like Thomas Morgan and others.
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But for a long period of time, nothing happens and nothing's relevant. What you see in this book is
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very different because you see a sort of continuation of development. So once the microscope is invented
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in the 17th century, you see from the 17th century a kind of gradual blossoming of the science,
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ultimately ending up with someone like Rudolf Virchow, who can make really audacious statements that
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are missing in the history of genetics until much later. The audacious statement that Virchow makes is
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every function that we carry out, regardless of its origin or regardless of what that function is,
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is a consequence of cellular physiology. We ourselves and everything that we do is cellular,
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is a consequence of something happening in some cell. This conversation is a consequence of something
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happening in some cell. So that's one piece, that's statement one. And then you get the other
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converse statement, which is equally audacious, in which he says that every illness is the consequence
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of some cell behaving incorrectly. And these statements are made in the mid to late 19th century.
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They're in fact almost contemporaneous with Mendel. So you have enormous sets of leaps in cell biology,
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which is why this book might feel that these characters are doing things while genetics is
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still plodding its way, trying to understand Mendel's first very important paper. And there's a
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remarkable 40 years of silence, whereas in cell biology, there isn't that 40 years of silence.
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And I think also, maybe we take it for granted sometimes today, but the ingenuity that was
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necessary to even build the tool to permit the visualization. I mean, we just glossed over the
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fact that in the 17th century, we're putting together microscopes, but you actually describe in
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some detail what the process is like to grind the glass, to create the lens, to even have the window
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into this otherwise microscopic and invisible to our eye piece of physiology.
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It's an incredible, I tried to make one myself. I tried to make one of Lewin-Hook's microscopes.
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And I can tell you, Peter, it was not an easy task. It was a disaster. And he made 500 of them.
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These are single lens microscopes, and they're about this big. It's about the size of half a sheet of
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paper. And the lens is smaller than the size of your eyeball. So you have this sense in which you
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have an enormous amount of labor of love put into making this thing that's mounted with tiny screws
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and tiny little apertures, so that when you look through your eye, through the lens in a droplet of
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water, you can actually see these microscopic forms. So there's an enormous sense of wonder about how
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people even began to see these and how they found them and what the consequences of that finding
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were and are. People who listen to my podcast are probably used to an idea that I talk about.
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And you have come across this now, Sid, because you were kind enough to be one of the people who
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read my book. But I talk about this transition from medicine 1.0 to medicine 2.0. And then,
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of course, where I hope we're going is the transition from 2.0 to 3.0. And I typically talk
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about medicine 1.0 to 2.0 as two big events happened. And they weren't momentary events,
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they were transitions of process. One was, of course, the way we changed the way we thought,
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right? So it was the scientific revolution. So once we introduced the scientific method,
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late 15th century, we had a new way of thinking about observation and hypothesis. And all of a sudden,
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the idea of bad humors and all that stuff sort of went away. But really, the big moment became germ
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theory. Once we understood microbial agents and that we had a way to treat them, we really
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leapfrogged into the era of modern medicine. And if you look at the mortality rates as a result of
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that, it's outstanding. I mean, there has been no bigger reduction in human mortality than the
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reduction of death that comes from infectious diseases. What I had never really thought of until
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I read your book was that couldn't have happened without this deep understanding of the cell. I mean,
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it's obvious when I say it that way, but in effect, this book describes how medicine went
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from effectively witchcraft into where we are today. We're going to talk about this in more
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detail, by the way, but does that make sense to you? Oh, absolutely. It makes sense to me in the
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sense that it makes sense because the introduction of being able to ultimately see germs and connect
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germ theory with human disease, as you say, took medicine from witchcraft to the modern era.
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Think of any procedure, childbirth, any surgical procedure, anything that we do, and think of the
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effect of antibiotics on that procedure and think of how important it is that these antibiotics are
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now available and the lifesave. I mean, just childbirth alone, the capacity of saving lives through
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antibiotics has been enormous and transformative in terms of, as you say, moving medicine from witchcraft
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itself. What's astonishing in the piece that I write about microbial biology and the discovery
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of microbes, Peter, is that microbes were imagined in the abstract long before they were seen. So
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what's interesting is people like Lister, the great surgeon who began to sterilize his instruments,
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folks like Semmelweis, and I have a small biography of him in the book, almost ignored by medical history
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now. But Semmelweis discovered that doctors were transmitting microbes.
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Tell the story. I have it in my book. You have it in your book. I'm really glad that more and more
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people are writing about him because it always breaks my heart when someone dies without their due.
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And Semmelweis is the example of that. And it's a heartbreaking story, but it's a remarkable example
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of this transition. So Semmelweis was a junior obstetrician in Vienna. It's important that he was
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so junior. And he made a very important and incredibly important discovery. So Semmelweis was
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delivering children. And there were two maternity wards, ward one and ward two. And this is why it's
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important in medicine, I think, to listen to your patients. You know, the famous adage in medicine is
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the most important question that you ever ask in medicine, when you're trying to diagnose a patient
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is to ask the patient, what do you think the problem is? And it's the one we forget the most,
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right? Doctors never ask that question. But usually the patient will tell you. They'll say, you know,
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I think I have an infection in my lungs, or I think I'm depressed because of X or Y reason,
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because I lost my father. So Semmelweis learned to ask people of a bizarre aberration that was going on,
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which is that in ward one, the maternal mortality rates from childbirth were astronomically high,
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whereas in ward two, same people, same women coming in were much lower. And he knew this because,
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you know, at least the story goes, whether it's apocryphal or not, that in ward one, mothers would
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beg to be admitted into the safer ward, while they would beg not to be admitted, where they would have
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a 30% mortality rate, or a 20% mortality rate, one out of five women. I mean, it's an incredible number
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if you think about it. So Semmelweis began to ask the question, why? And he looked at all sorts of
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variables. He was sort of a classical epidemiologist. So he looked at all sorts of variables. And the
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variable that he found was that in the first ward, where there was a high mortality rate, it was run
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by doctors. And these doctors, he figured out, were running between autopsy rooms, doing autopsies on
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probably the very patients that they had killed, and then running, and then without cleaning their
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hands, delivering babies, essentially examining patients, delivering babies, etc. Ward two, on the
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other hand, was run by nurses. Nurses were not doing autopsies, not touching any decaying or dead
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material. And there was no mortality. So Semmelweis made the hypothesis, again, remember, this is a
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junior obstetrician in Vienna, that what doctors were doing is they were transferring, and these are
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his words, some material substance from the decaying, decomposing dead bodies that they had autopsied
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into the bodies of the women that they were examining internally, and thereby transmitting that
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material substance. And that material substance was the source of the putrefaction or the infection
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that these women were getting. And he insisted that the doctors wash their hands with a diluted
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version of bleach. And he saw that suddenly, now the mortality rate plummeted. And so he made this
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argument. Now, remember, he didn't have a microscope. It is all in the abstract. But he made this argument
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that this material substance was responsible for what was then called childbed fever or maternal
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infections. And the transfer of the material substance could be removed by handwashing. So in
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the abstract sense, he had basically founded germ theory. Completely prescient.
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Yeah. And the idea of a material substance, that's what's important about it.
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Right. It wasn't just bad air in a vague sense.
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It was not bad air. It was not bad humors. It was a material substance. And of course,
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if he had the capacity to look down the microscope, he would have found out that that material substance
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was in fact nothing else but germs. And the sad thing, the epilogue to the story is the guy dies
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in an insane asylum, basically having been ridiculed. That's right. So he's ridiculed. The last thing that
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the doctors want to do is to admit that they've been infecting other women. So Samuel Weiss is ridiculed,
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and he's sent off to an insane asylum. And ultimately, he dies impoverished and never vindicated.
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Medicine is full of these stories. But this is what it was about the book that really captivated
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me. This thing that I've taken for granted so much of my existence in medicine is what really allowed
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this leapfrog. And frankly, far more so than the genetic revolution. I mean, we could sit and talk
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about has the genetic revolution delivered on its promise. In some ways, yes. In some ways, no. We
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thought whatever it was 22 years ago when the human genome was coded, that was basically going to be
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an equal leapfrog forward. It turned out not to be. We'll come back to talk about some genetic stuff.
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But I want to go back to a question that you pose in the book that I had never contemplated,
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and I have not been able to stop thinking about it, and I love it. Which is,
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what's the evolutionary drive for multicellular life? We go from these single-cell organisms
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that have all of their own evolution built into them, and then look at the complexity that we are
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today. You go through this very elegantly. Let's pause for a second to contemplate single-celled
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organisms. So they are bacteria, protozoa, yeast, et cetera. They're extraordinarily successful.
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You can't imagine how successful they are. They live in virtually every environment that you can
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think of. You know, they live in boiling water. They live in thermal vents. They live in inside
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volcanoes. They live, I mean, how successful is a single-celled organism? The bizarre question that
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you should ask is why we exist at all? What is the reason that we have trillions of cells? Why do we
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exist? Why aren't we all bacteria? And people have been trying to answer the question. And the initial
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idea in the 80s was that there was a massive leap, evolutionary leap, from single-celled organisms
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to multicellular organisms. But what's surprising is that if you look at evolutionary history, and if
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you look at all the evidence from evolutionary history, it turns out that multicellularity evolved
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from single-celled organisms not once, but independently multiple times. It used to be called a major
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transition. It actually turns out to be a minor transition. In other words, there was a great
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evolutionary drive towards becoming multicellular. And you can ask the question then, well, if single-celled
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organisms are so damn successful, why ever be a multicellular organism? The quick answer is we don't
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know, but all the evidence suggests that it has to do with several possibilities. The leading possibility
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is predation. It's much harder for a predator to eat a multicellular organism for several reasons. One
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of them is that it's bigger. Number two is that it has defense systems. Number three is that it can move
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away from predators through specialized apparatus. So that's one idea. The other idea is food and
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resources. Multicellular organisms can access food and resources. And there are other ideas about how
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multicellular organisms came to exist and essentially conquered the world, as we know. But that said,
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single-celled organisms are still the champions. We are just a minor fixture in the world. If you took
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by weight all the single-celled organisms in the world and their diversity, you would be shocked at how
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successful you still are. Remind us what Ratcliffe's experiments with yeast demonstrated. I had never
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heard of that experiment before, so I'm reading this like I'm reading a thriller novel.
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William Ratcliffe is a professor who studies this evolutionary transition from single-celled to
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multicellular organisms. And he did this, actually, an extraordinary simple experiment. And he just
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thought about it over Christmas with Travizano, his advisor. He said, well, why don't we just take some
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yeast and culture them? And we basically allow them to grow. And so, remember, yeast are single-celled
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organisms. And we just collect the sediment. So, anything that's multicelled is obviously going
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to sink to the bottom of a flask. We collect the sediment. And then we allow that sediment to grow
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again in another cycle of evolution. So, this is sort of Darwin in a bottle. So, we allow that to
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evolve another cycle, collect the sediment, allow that to evolve another cycle. And by about 30 or 40
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cycles, he found that the yeast had evolved. And this is astonishing. I have pictures of this in the
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book, into these sort of snowflake-like, multi-fingered, multicellular forms. Really a
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new organism, a multicellular yeast. And what's interesting about them is that when he let them
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be by themselves, so no more recollection, no more sedimentation, they continued to propagate as
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multicellular yeast. So, in other words, he had basically created a new life form, which is
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multicellular. And what is even more interesting is that when he looked at these multicellular yeast,
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they started to acquire specialized functions. So, you would imagine that one way that these
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multicellular yeast could reproduce is that one cell could butt off and create a new multi-fingered,
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multicellular yeast. That would be one way that these organisms could reproduce. But that's not how
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they reproduce. The way they reproduce is that a specialized series of cells that sit in the middle
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of this snowflake, commit a purposeful cellular death. I repeat the word, they commit a purposeful
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cellular suicide such that this snowflake can break into two parts, two snowflakes, and grow out new
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fingers. So, this organism has now, evolutionarily speaking, learned. The word learned implies that it
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has some consciousness, but that's not true. This is just an evolutionary process. It has created a
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specialized furrow in its middle, where these cells basically can divide into two forms. And what's
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more is that he's now, Draxler has done many versions of this experiment. He's done it with algae. He's done
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it with various other organisms. And what he finds is that there's even more specialization. So, these new
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creatures, that's the only thing I can call them, form little channels to deliver nutrients. They form pores.
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They form secondary structures. He's really sort of created a new kind of life. And just by doing
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nothing, I mean, just by allowing it to evolve naturally. And remember, this is 30, 40 cycles,
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which may be 60, 80, 90 days. So, you can imagine over the course of several billion years of history,
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the extraordinary amount of diversity and specialization that could happen in evolution that
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leads to people like you and me, having trillions of cells, very committed to doing one thing or
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another thing or many other things. Because my kids, who were five and eight at this point, they're,
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as you can probably imagine, obsessed with dinosaurs. So, we're nonstop watching every
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imaginable thing. Paleontologists are the most important people in the world at this point.
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I can't help but wonder when I watch these recreations of what we assume dinosaurs to have
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looked like. I mean, at least we know about their size. How did evolution allow something so large
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to be in existence so many millions of years ago? And are we basically seeing a correction now? In other
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words, was that just the pendulum swinging too far towards multicellular, where here you have things
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that can really defend themselves, that can really get away, that can really go after prey, but of course,
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they're too sensitive to a reduction in food or something like that? Or is that just totally
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unrelated? And had it not been for volcanic eruptions and things like that, maybe we just
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wouldn't be here today and dinosaurs would be the sentient higher order creature?
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A little bit outside my pay rate in some ways. But you know, there's lots of theories. I'm certainly not a
00:24:32.800
paleontologist. So, there are lots of theories about the extinction of dinosaurs. What we do know is that
00:24:38.700
these life forms were also very successful in their environments. The problem was, as many people have
00:24:45.760
hypothesized, that they reached a maximal capacity of size. And smaller mammals or mammal-like creatures
00:24:54.480
became much more adapted or adaptable to the environment. But there are a thousand theories about
00:25:00.280
dinosaur extinction, including changes in the atmosphere, meteors, and various other volcanoes and
00:25:07.600
events, which you can read in most paleontology textbooks.
00:25:11.760
I just wonder if there's something about their size that became their downfall beyond the obvious
00:25:18.060
external factors. And it just made me think of that when I was reading that segment about
00:25:25.100
There's a beautiful essay, if I remember correctly, by Stephen Gould, where he talks about a natural
00:25:32.520
biophysical limitation on size. And that's because the volume to surface area of any creature reaches a
00:25:41.580
place where the volume to surface area becomes no longer sustainable, because the surface area of a
00:25:48.100
creature is no longer able to deliver the oxygen and the nutrients required for aerobic living.
00:25:56.300
I'd encourage people to read it. I don't remember the name of the essay, but...
00:25:59.980
We'll find it. It has to do with a rhinoceros and what the size limits of creatures can or cannot be.
00:26:07.000
Interesting. So let's go back to something in the book where you talk about the four types of cell
00:26:12.220
therapy. When you spell it out, it sort of makes sense, but I'd never considered this before.
00:26:17.920
I think it's an illustrative framework for people to think about the era of medicine that we live in.
00:26:22.660
So what are these four areas of cellular therapy?
00:26:25.280
I tried to create a typology of the four types of ways in which we could use cells as medicines.
00:26:33.640
The first is the simplest one of all, which is to use a drug or a substance to change the behavior
00:26:38.960
of a cell. So the simplest example would be an antibiotic. You're using a drug to kill
00:26:44.940
a microbial cell while you're sparing normal human cells. That's one. The second one is the transfer of
00:26:52.740
cells from one body to another body without any modification. The simplest example of that would
00:26:58.200
be blood transfusion. So you're transferring red blood cells, platelets, and other cells from one
00:27:03.740
body to another body for therapeutic effect, but you're not essentially changing the cell itself.
00:27:09.380
The third is the use of a cell either transferred or by itself in a dish, in a bioreactor, in a chamber
00:27:17.440
to synthesize something. So I remember I said that DNA is inert. It's a lifeless molecule. If you put it
00:27:23.680
inside a cell in the right context, the right cell in the right context, the cell will start making
00:27:28.140
proteins out of DNA. And those proteins could be very useful. So the insulin, for instance, you can only
00:27:35.140
make insulin in cells or you can, that's how insulin is generally made. Antibodies are made by cells.
00:27:41.880
The antibody receptor that you use in breast cancer is made by cells. So that's a third use. And the
00:27:47.920
fourth and the final is the one that is coming up and now becoming more and more prominent as we move
00:27:53.220
into this new era. And that is the use of a cell where you make a genetic modification in a cell
00:28:00.220
and then either transplant it or use it for a therapeutic reason. So for instance, our T cells,
00:28:08.020
which I'm sure we'll talk about, are examples of genetically modifying T cells and putting them
00:28:14.480
into a human body. I've been doing, as you very well know, a series of experiments on bone marrow
00:28:21.500
transplants in which we genetically modify the bone marrow using CRISPR and other techniques and then
00:28:27.260
transferring them into human bodies and essentially creating genetically engineered cells. People often
00:28:34.280
talk about gene therapy and I always remind them that gene therapy is really cell therapy.
00:28:40.360
If you put the gene in the wrong cell in the wrong place at the wrong time, you get nothing. You get
00:28:45.500
the disaster. So gene therapy is really a mechanism to put a gene inside a cell and that would be the
00:28:52.800
fourth typology, as it were. And then the book goes through elements of these four typologies,
00:28:58.620
examples and elements of these four typologies as medicines.
00:29:01.880
Well, let's touch on a few of them because you and I don't have the ability to sit here for the
00:29:06.820
next three days, which is what it would take to do each of these, their appropriate service.
00:29:11.220
There are a handful that I really want to talk about. So let's talk about the story of Jesse
00:29:15.920
Gelsinger because that is one of the earliest examples of gene therapy in a human. We could talk
00:29:23.420
about what went wrong, but let's use Jesse's story just as much to explain the state of the
00:29:27.920
technology at the time, the vectors, the vehicles, the methods by which genes were transferred. So
00:29:33.760
let's just start with kind of what disease did Jesse have? Why was gene therapy viewed as the
00:29:39.740
solution as opposed to whatever the other three methods would have offered Jesse?
00:29:44.740
So Jesse had a genetic disease. He was a young kid, I think 14, 15 years old, 16 maybe. And I've had a
00:29:52.660
very, very, very moving interview with his father. He had a defect in an enzyme, which is related to
00:29:59.780
the processing of ammonia and ammonia related substances in the body. The idea back then, and we're now
00:30:07.900
talking about 22 years ago. Yeah, it was about 2000. Yeah. At the University of Pennsylvania, the idea was that
00:30:15.520
if they could create a virus, which would then go to Jesse's liver and start making the correct version
00:30:24.520
of the gene, then Jesse's disease would be ameliorated. So they created a virus that they thought was going
00:30:30.700
to be harmless. It was a variant of an adenovirus. And then they genetically modified that adenovirus to
00:30:38.200
now include the corrected version of the gene that Jesse had a problem with. And then they infuse that
00:30:45.500
virus into Jesse's body, hoping that the virus would go and infect because viruses infect cells
00:30:51.120
and deliver its cargo. The cargo would be the corrected gene and thereby correct Jesse's disease.
00:30:57.500
So that was the idea behind that therapy. Let's explain two things before we go on with the story.
00:31:03.940
We didn't say this earlier, so I think it's worth clarifying. We don't really consider viruses in the
00:31:09.840
same category as bacteria, yeast, fungi. Why is that? Do we consider them living things? Are they not
00:31:15.500
living things on their own? I mean, they basically just contain DNA and RNA, but they're sort of
00:31:19.980
parasites in it they need us to replicate? That's right. So viruses are not, they don't meet the
00:31:25.880
criteria of living things. They are essentially a strand of RNA or multiple strands of RNA or DNA
00:31:34.660
that have been packaged usually with an envelope and decorated with some proteins on top. But they,
00:31:41.880
by themselves, they can't reproduce. They can't make copies of themselves, which is one of the
00:31:45.960
reasons that they're not considered living. The only way they can reproduce is they go and attach
00:31:50.460
themselves to cells, let's say to human cells or any other cells. And then they use the reproduction
00:31:58.740
apparatus, the duplication apparatus and the reproduction apparatus and the synthetic apparatus that's present
00:32:06.200
in the cell to make copies of themselves. And once they've made copies of themselves, they bud out of
00:32:12.280
the cell, and then they go and infect more cells and make more copies of themselves and so forth.
00:32:16.920
That's what a virus is. And in Jesse Gutzinger's case, the idea was that this virus would essentially
00:32:22.280
infect his cells. And because the virus was genetically modified, it would insert its genetic payload,
00:32:29.300
which consisted of the normal gene into Jesse's liver cells. The liver cells would now start making the
00:32:35.060
protein that was defective in Jesse's case. This is gene therapy. And then in doing so,
00:32:45.780
So what happened then? They used this adenovirus, they injected him, and it went pretty bad pretty quick.
00:32:53.020
Yeah. So a rather terrible thing happened. And again, I have a very moving testimony from his father,
00:32:58.480
which is in the gene, a little bit in this book, but really in the gene, a terrible thing happened.
00:33:03.120
So in retrospect, we think what happened is that Jesse mounted a very vigorous immune response.
00:33:12.160
A virus is a foreign object, a foreign body, and you mount an immune response to it, especially
00:33:17.160
if you, for whatever reason, have been exposed to that virus before. And people now suspect,
00:33:23.560
we don't know for sure, adenoviruses cause common colds, they cause, you know, incirculation. There's a
00:33:30.200
suspicion that Jesse had been exposed to that virus, the wild form of that virus before, perhaps through
00:33:38.140
a common cold or something like that. And his immune system went berserk. Because it was now recognizing
00:33:44.660
not one virus particle, but millions of particles suddenly into his body. His immune system went berserk.
00:33:52.120
And when the immune system goes berserk like that, you basically have terrible consequences because
00:33:57.400
your body is recognizing your cells as foreign, the virus is foreign. It goes on what I call a kind
00:34:03.880
of immune rampage. And that immune rampage can kill you. And unfortunately, Jesse died from the
00:34:10.600
consequences of this very hyperactive, brisk immune response raised against that virus. And in fact,
00:34:17.400
the whole field of gene therapy was frozen for almost a decade as we learned to slowly understand
00:34:25.120
the cause of that death and how we could prevent it in other people.
00:34:29.320
So I think in response, the field said, look, we need to look at slightly more immune protected or
00:34:35.600
privileged sites to dip our toes back in the water. Tell folks a little bit about what's a safer place
00:34:42.140
to maybe consider gene therapy as the field moves closer to that.
00:34:46.440
Well, there are many things that have happened. It's not just safe places. So I'll give you some
00:34:49.940
examples. Again, I'll try to create a typology for you. So one thing you can do is there are safe
00:34:55.100
harbors in the body. By safe harbors, I mean places that the immune system doesn't usually reach
00:35:00.620
easily. The retina turns out to be one of them. There's not a lot of immune cell infiltration into the
00:35:06.620
retina. So you have a chance to use gene therapy. And in fact, there are now several gene therapies
00:35:12.000
that have been approved that allow you to insert or inject viruses so that you can correct a gene
00:35:18.840
that's missing or abnormal in the retina. So that's one place. There's some other places in the body.
00:35:24.380
Turns out the testes is another place, although we've not used that for gene therapy. That's one thing
00:35:29.620
you can do. The other thing you can do is there are new drugs that can dampen down or tack down the
00:35:36.800
immune response. So you can think of the immune response as a dial. What you can do is you can
00:35:41.640
dial the immune response down so that the immune response doesn't respond so briskly to the gene
00:35:48.840
therapy. You can hide the virus. So you can make a virus such that your body has not seen such a virus
00:35:57.000
before. So you can actually use a novel kind of virus that won't raise a brisk immune response.
00:36:02.700
The fourth thing you can do is you can actually give the gene therapy in small doses. It's called
00:36:08.760
hyperfractionation, fractionation being small fractions, so that the immune system doesn't
00:36:14.260
again go berserk, seeing this massive bolus of a dose of virus. So those are some of the strategies,
00:36:21.380
and they've been very successful. So that now the number of deaths from this hyperactive immune
00:36:27.200
response still remain, but they are much, much, much more controlled than in Jesse Gelsinger's times.
00:36:33.720
So you alluded to an example earlier of CAR T-cells. I think it's one of the great successes of cancer
00:36:39.600
when it comes to treating CD19 or B-cell cancers. Let's use that as an example to explain
00:36:45.200
how gene therapy can work in that regard. Well, so CAR T-cells are a very special example
00:36:50.980
of gene therapy. So in a CAR T-cell, what happens is that you extract T-cells from a human being who
00:36:58.240
has cancer. You extract their normal T-cells, and you use gene therapy to weaponize them so that they
00:37:06.200
can attack cells, including cancer cells. So you're essentially turning a T-cell. A T-cell is part of
00:37:13.280
the immune system. Its job is to hunt out and kill foreign cells, including cells that have been
00:37:19.480
infected by viruses or foreign cells that have somehow entered the body. That's their job. That's
00:37:25.000
the job of a T-cell. It's a foreign cell detector built into your body. So now you take that T-cell
00:37:31.440
and weaponize it to recognize the cancer cells as foreign, and then you re-inject them. You grow them
00:37:38.100
in a petri dish in the laboratory, and you re-inject them into the body. And, you know, our laboratory
00:37:43.080
has done a lot of this work. We are now doing this in India. The costs of doing this are astronomical
00:37:49.280
in the United States, almost $500,000 to a million dollars per person. We're trying to reduce that
00:37:56.460
cost dramatically, 20-fold, perhaps even 50-fold in India using new technologies, etc. We've treated
00:38:02.400
about 11, 12 patients already, and we've just released the data. It looks very good. They're
00:38:08.020
usually used in blood cancers like lymphoma, leukemia, and myeloma. They've not been so
00:38:13.800
successful in solid tumors for reasons that we don't fully understand that we're still trying
00:38:18.760
to understand. But that's what a CAR T-cell is. It's a weaponized T-cell that goes and kills cancer
00:38:24.960
cells in your body. What is the difference? Why is there a 20 to 50-fold reduction in cost doing this
00:38:32.440
in India as opposed to the United States? Because this is, of course, one of the jugular issues with
00:38:37.760
oncology is marginal treatments. Not that I'm saying CAR T-cell is marginal. It's actually one of the few
00:38:44.040
beacons of success. But cancer is full of marginal treatments, you know, extend median survival by two
00:38:51.140
months at a cost of $100,000. How much of that is just a structural American problem versus people that
00:38:58.200
are able to go outside of the existing channels of IP? Some of it is a structural American problem
00:39:03.180
and some of it is not. So obviously, the structural American problem is that for reasons that we're
00:39:10.280
trying to still investigate, 90% of drugs, including drugs in the cancer space, fail. And pharmaceutical
00:39:17.240
companies make the argument that they're trying to recoup the R&D costs of those failed drugs with the
00:39:25.500
ones that are successful. Now, that's a complicated and I would say somewhat specious argument because
00:39:30.720
you could say to them, well, why did these drugs fail in the first place? Is it because drugs always
00:39:35.760
fail? Is it because you didn't understand something about the human body that you therefore took this
00:39:41.460
drug all the way to spend millions, perhaps even billions of dollars on the drug? So that's one reason.
00:39:47.980
So that would be the standard argument. The second reason is that CAR T's are intrinsically expensive
00:39:53.680
to make. Their success rates are incredible. So these are not just one month, two months survival.
00:40:00.040
My book begins with the story of Emily Whitehead. She was seven when she was treated with CAR T therapy.
00:40:05.180
She's now 17 or 16, applying to college, completely cured. So you have a situation in which these are
00:40:12.980
miraculous drugs. We've seen people who've had terrible leukemia, essentially eradicated leukemia forever
00:40:20.560
and become cured. The problem is that they're intrinsically hard to make. To weaponize the T
00:40:26.820
cells, you need to make a virus. The virus is expensive to make. It's labor intensive. The quality
00:40:32.200
control that's required is much, much greater than, you know, making aspirin or making any other
00:40:37.660
tablet. And then, of course, growing the T cells, you have to grow them in an incredibly sterile environment
00:40:43.120
where you have to basically put on a hazmat suit to go in. It's called a GMP facility, but it's a
00:40:49.380
highly, highly sterile environment. It has to be monitored. It has to be checked. A single bacteria
00:40:55.220
or a fungal infection in that flask of a T cell will now basically take that entire batch away.
00:41:02.120
You can't give those back. So there are some intrinsic expenses. Now, you asked the question,
00:41:07.660
how can you reduce the cost? Well, we reduce the cost by several ways. One is that we've learned to
00:41:13.440
make the virus in a much cheaper way. We've reduced the cost of the patent burden by essentially really
00:41:22.200
making successful products and not spending millions of dollars on unsuccessful products,
00:41:27.040
so we don't have to recoup all that R&D cost. We've changed the machinery. We've changed the way the
00:41:33.920
cells are harvested. And finally, of course, hospital treatment and therapy in India is much
00:41:38.780
cheaper to start off with. Adding them all together comes to almost a 10-fold to 20-fold reduction in
00:41:45.120
cost. Let's now use another example of gene therapy, which is maybe the harder of the problems.
00:41:52.280
You have a person more like Jesse, where they have a germline mutation that results in a pathology.
00:42:00.000
And the goal is as an adult, let's pick sickle cell anemia as an example. In some ways, sickle cell
00:42:07.900
is so amazing that one single amino acid difference can have such catastrophic consequences on the life
00:42:15.260
of a person. But you want to now just change that. I mean, it's a single amino acid. We know exactly
00:42:20.820
what genes drive that. How does one go about doing that? And where are we in the realm of approaching
00:42:27.120
success there? Fantastic new results in sickle cell anemia published in very major journals and will
00:42:34.720
continue to get published. Ancient disease, as you know, single amino acid mutation. If you inherit
00:42:40.180
two copies, then you get sickle cell anemia, a terrible disease. Your blood cells in low oxygen
00:42:46.340
environments form sickles. They basically clog up. It's like plumbing clogging up. And you get essentially
00:42:52.540
what you might consider micro strokes all over the small blood vessels in your body. Terrible pain
00:42:59.560
associated with it. So the answer would be in gene therapy, what if you could change the mutated gene?
00:43:06.780
So there are two or three approaches that have been so far tried. One is using new technologies,
00:43:13.840
gene editing technologies, to basically change both copies of the gene to now make them into normal. So
00:43:20.040
take out your bone marrow, which is where blood is made, change the gene from the abnormal gene to the
00:43:25.920
normal hemoglobin gene, then re-infuse that back into the patient. So that's a gene correction strategy.
00:43:34.020
There's another strategy which is very attractive and fascinating. And I'll just briefly mention it.
00:43:40.380
So it turns out that the fetus, the human fetus, has a special kind of hemoglobin, which is different
00:43:46.340
from adult hemoglobin. And the reason it's different is that the fetus has to extract oxygen from mom's
00:43:52.780
blood. And mom's blood, by the time it reaches the fetus, has already been depleted of oxygen because
00:43:59.140
it's gone through her body. So this is called fetal hemoglobin. Basically, the fetus has a special form
00:44:04.920
of hemoglobin, the oxygen carrier in blood, that can even extract oxygen out of mom's blood.
00:44:12.000
And so another approach to sickle cell anemia is to forget about the sickle gene problem and basically
00:44:20.440
in an adult somehow reactivate or express or make fetal hemoglobin. In that case, you don't need to
00:44:29.520
correct the gene. You leave the gene as it is. You just make fetal hemoglobin, which is very, very avid
00:44:36.060
as an oxygen delivery machine. And the cells don't sickle anymore because they don't have this
00:44:41.500
oxygen problem. And that too has been successful. There have been several trials now showing that if
00:44:47.060
you activate fetal hemoglobin, you can do that. So just to summarize then, you can either do gene
00:44:52.900
therapy to express the corrected version of the sickling gene. The gene is called beta globin.
00:44:59.060
That has been performed. The second approach is to use gene editing technology to change the gene back
00:45:06.100
to its normal form. And the third approach is to reactivate fetal hemoglobin in adults to essentially
00:45:12.780
correct the hemoglobin defect. And all three of them are in trials. And all three have shown various
00:45:18.420
measures of success. My impression is that during our lifetime, we'll see a cure, a permanent cure for
00:45:24.160
sickle cell anemia. So this dovetails nicely into, I think, a term that most people have heard of,
00:45:30.800
but the details of this are pretty important. And this is the idea of CRISPR. Now, I haven't had
00:45:35.900
Jennifer Doudna on the podcast yet. I would love to at some point. So we don't need to necessarily go
00:45:40.000
into the great depths of CRISPR. But I think some history is probably relevant, especially as it
00:45:45.880
pertains to the topic of our discussion, which is cells, bacteria and viruses, or bacteria as the
00:45:51.180
cells and how they interact with viruses as a way to protect themselves. But I now want to use the
00:45:55.120
story of CRISPR to talk about another tool by which one can impart this type of cell therapy. So
00:46:00.580
So the world of genetics was turned upside down in a very important way by the discoveries of
00:46:08.480
Jennifer Doudna, Emmanuel Charpentier, and several others. I should mention Feng Zhang and George Church.
00:46:15.960
And there's a history of this, which is in the book. For a long time, there was the question,
00:46:23.960
so the human genome is a library. Imagine the human genome as a massive library. If it was
00:46:30.260
printed in normal text, it would contain 80,000 books, a massive encyclopedia, stretching across
00:46:39.280
a massive library. And imagine that you wanted to make a change in one word in that library.
00:46:47.320
You want to take book 61 on shelf 47 and make a change from verbal to herbal in that library.
00:46:56.380
This was a dream of scientists for a long time, and no one could do it. And then Jennifer Doudna,
00:47:03.400
Charpentier, assisted by Feng Zhang and other people, figured out that there was a bacterial system
00:47:10.320
evolved millions of years ago that could make that precise change in one word in that entire library,
00:47:19.740
either deleting that word, in other words, erasing it, simplest change, or potentially changing the word to
00:47:27.120
another new word. It's an incredible genetic revolution. So as we move forward into this new
00:47:36.340
universe, we have the capacity to change the human genome in a deliberative and a processed manner.
00:47:46.140
So just take the example of sickle cell anemia that we gave before. We can change that sickle cell
00:47:53.060
anemia gene to a normal gene by using this technology. We can change a mutant or abnormal cystic fibrosis
00:48:02.740
gene to a normal gene, the normal version or the wild type version using this technology. So it's
00:48:10.300
obviously extraordinarily important. And there are many, many applications of this technology.
00:48:16.820
And it's exciting because we can do things that we couldn't do before involving changing genes to new
00:48:25.820
genes, changing genes to their wild type variants or their more common variants and so forth.
00:48:33.000
So we now have the capacity to do this. We can do this with embryonic cells. We can do this with embryonic stem
00:48:41.920
cells. We can do this with bone marrow cells, T cells, CAR T cells. It's a revolution. And all I can
00:48:49.920
emphasize is the depth and breadth of this revolution because it's enormous.
00:48:56.040
Two follow-up questions. The first is, explain using the library analogy, how this system differs
00:49:02.720
from the approach that was used 20 years ago in the case of Jesse Gelsinger that we described where
00:49:09.300
an adenovirus was used. I mean, what's the difference in scale and elegance between what you just described,
00:49:17.180
which is in the 80,000 books, you can go to one page, one word and make the change versus that other
00:49:23.260
approach. So again, imagine the human genome as a massive library, 80,000 books printed on a page.
00:49:32.600
So the old technology, the technology that was used with Jesse Gelsinger is the technology in which we,
00:49:40.740
I'm using metaphors and analogies here, we would insert a new page into that 80,000 page library.
00:49:49.140
So you would go into the library, 80,000 books around you, and you would take a page and insert
00:49:56.140
a new page, a foreign page into that library. The librarian could come, in this case, the immune
00:50:03.300
response, the T cell or the B cell immune response and come and say, wait a second, that's not a page
00:50:09.560
that belongs. And that's what happened with Jesse Gelsinger and other people, librarian being the human
00:50:14.940
body would come and say, wait a second, you're inserting new pages into a library. That's no
00:50:21.060
good and would prevent that. And it seems to me that it was much harder to know where to put that
00:50:27.320
page. I mean, if you knew a priori, I really want that to be between page 87 and 88, you might
00:50:34.520
accidentally insert it somewhere else, right? Exactly. And the librarian would say, well,
00:50:39.160
why are you putting it into Jennifer Egan's book on the Goon Squad? It doesn't belong there. You've
00:50:46.400
just inserted that new page, the new gene into a place where it doesn't belong. And he or she would
00:50:53.640
say, I don't buy this. I'm not going to let you do that. That's absurd. You're reading along with
00:50:59.980
Chekhov or Egan or whoever. And all of a sudden, you find a new page that's been taped in the virus
00:51:07.200
that's carried in the new gene, the new virus. And you say, well, wait a second, that doesn't
00:51:12.360
belong there. And that was where the technology sat for years and years and years. Then Jennifer
00:51:18.680
Doudna, Charpentier and others discovered a method in which you would do just quite the opposite.
00:51:26.040
You would go into a page and say, listen, I have the right page in the right volume of the right book,
00:51:33.600
and I'm going to change one word. The first kind of word that they could change was just
00:51:39.540
deleting a word. And this was using a viral system called CRISPR, and you could just erase a word.
00:51:47.360
And then more and more research showed that you could change the word. And as I said,
00:51:52.980
you could change the word verbal to herbal by changing a single letter and for the most part,
00:51:57.940
leave the library intact. And if you were a very vigilant librarian, you would say,
00:52:03.960
that's okay. You haven't put in an extra page in Charles Dickens' book. You've actually gone to
00:52:11.240
the right book and changed the right word in the right space, in the right time, from one to another.
00:52:18.620
And that's the subtlety of what CRISPR allows us to do. It allows us to make extraordinarily precise
00:52:26.360
changes in extraordinarily precise ways in a massive library, which would not be possible otherwise.
00:52:35.020
So you alluded to this at the outset of your description, which was you could make changes
00:52:39.420
to an embryo. You could take an embryo and you could make a genetic change, which now has pretty
00:52:47.280
significant consequences because it is now a germline change. This is different than if you made a change
00:52:54.460
in a non-germline cell way down the line. And I guess as things would have it, the first documented
00:53:01.580
example of this created quite a controversy. Maybe briefly tell the story of JK and the CCR5 gene.
00:53:10.460
More importantly, what are the implications of that pretty unethical episode?
00:53:16.120
Again, I would encourage people to read the book, The Song of the Cell,
00:53:19.200
to get all the details about it. But a Chinese scientist, JK Hui, made a somewhat bizarre decision.
00:53:28.680
I'll talk about why that decision was bizarre. There is a gene in the human genome that makes
00:53:37.080
cells resistant to HIV infection. There are many genes, but this is one of them. The Chinese
00:53:43.840
scientists, scientists in this case, Hye-Joon Kan, decided that he was going to make a change in human
00:53:50.640
embryos with gene editing technology, the technology that I just described, which would make the child
00:53:58.080
of a parent couple in which the man was HIV positive, the woman was HIV negative, and make that change in the
00:54:07.560
embryo. And implant those altered embryos into the mom so that they would be HIV resistant because of
00:54:16.620
this change. So sounds great on paper. The problem is that their risk, the risk of these children to
00:54:24.220
acquire HIV because they were produced by IVF is basically zero. It cannot get HIV. The sperm doesn't
00:54:32.580
carry HIV. So if you produce a child by this method, you basically have a zero risk of HIV infection.
00:54:43.280
It wasn't medically necessary. Let me take a step back. I make a very big distinction between
00:54:50.080
disease and desire. Disease is fundamentally linked to suffering. When we talk about disease,
00:54:57.880
we talk about human suffering. When we talk about desire, we talk about the idea or aspiration to
00:55:05.840
ameliorate suffering, even where there's no suffering involved, as far as we can tell. Now,
00:55:12.900
in this case, there was no disease. The children had no risk of disease. They couldn't have any risk of
00:55:19.980
disease. The desire was an entirely scientific desire to create a genetically modified embryo. So in this
00:55:31.160
case, in particular, the desire was that they would create a modified embryo and that his inquiry would be
00:55:37.720
the first in human history to create a human embryo with genetically altered cells. So he went ahead with this
00:55:46.680
project, and he created two girls. We don't know their real names. They've been called Lulu and Nana. And what he obtained was not exactly what he hoped to obtain, which is not that precise erasure of verbal to herbal in a single book in the entire library of 80,000 books.
00:56:12.000
What he obtained was a much cruder version of that. And scientists across the world were concerned about, did he obtain informed consent? Did the parents even understand the language that we're using?
00:56:28.360
Now, remember, because this was an IVF procedure, the risk of these children getting HIV was zero.
00:56:35.200
So again, we come to the question of disease versus desire. They had no disease. The only desire was to create someone who was potentially resistant to HIV infection. So we have this situation, which is very unusual, where desire, the desire to change human embryos, the desire to push the frontiers of science, overwhelms the disease, where there is no disease.
00:57:00.960
And so the scientific world became extraordinarily incensed about the idea that this scientist had crossed the boundary between disease and desire. Now, if this had been some disease that the children had inherited, cystic fibrosis, sickle cell disease, Huntington's disease, some terrible thing that they would encounter in their lifetime, the scientific community would have been much more sanguine about it.
00:57:29.260
But these children, but these children, these twins that were born had a zero risk, zero risk of acquiring HIV from their fathers because the sperm had been watched. Sperm don't get infected with HIV. They had no risk of the disease. So what was left was desire, the desire to be first, the desire to create new human embryos. That's what incensed the scientists and the community of scientists.
00:57:58.180
You know, there's probably no greater example of the relationship between science and philosophy. People might want a little bit of a reminder about what a doctorate degree is formally called, right? A doctor of philosophy. When you think about this question, it becomes kind of difficult.
00:58:16.640
And I think in Walter Isaacson's biography of Jennifer Doudna, in your book, this topic is explored. Where does one draw the line? So, you know, Huntington's disease is a great example in the sense that you have an acquired genetic mutation that is 100% penetrable in a devastating disease that shortens life and leads to immense suffering.
00:58:39.680
Would we find many philosophers of science who would say that it is wrong to alter the embryos of adults who have Huntington's disease or carry that trait, that gene, to prevent it from going to their offspring?
00:58:56.100
Which, by the way, if you play the thought experiment out, would eliminate Huntington's disease altogether because these are germline mutations.
00:59:03.080
Like, how does the scientific and philosophical community merge over questions of that nature?
00:59:07.640
And then, of course, just to tell you, eventually, do we move that further to ApoE4, LPA, other genes that are not as penetrant?
00:59:15.180
Right. So ApoE4 is a risk factor for early Alzheimer's disease, just to give you an example of how devastating it can be for particular people who have combinations of ApoE4 and other genetic mutations that increase their risk for early Alzheimer's disease.
00:59:32.740
I think the scientific community would say, for Huntington's disease, the scientific community would say, listen, this is a devastating disease with a huge penetrance.
00:59:46.340
By penetrance, we mean if you inherit the gene, the chances that you'll have the disease is very high.
00:59:54.420
So you might inherit a mutation in some gene, whatever it might be, but you might not get the disease.
01:00:02.740
You might inherit BRCA1 gene, but you may escape having breast cancer in your lifetime.
01:00:09.820
Huntington's disease has a very high penetrance.
01:00:12.820
So in other words, if you inherit the mutation, the likelihood that you'll have the disease is very high.
01:00:17.960
I think the biomedical community would say that for diseases like Huntington's disease, it's probably worthwhile doing an intervention, whatever that intervention might be.
01:00:29.360
But the biomedical community would say that for, in this case, in HIV, it's not warranted.
01:00:37.460
And I think that the biomedical community would say it's not necessary.
01:00:41.740
It's not part of the continuum of disease versus desire.
01:00:46.420
It moves towards desire without moving towards disease.
01:00:50.140
I think the other examples of things on the clearly desire spectrum are pretty obvious, right?
01:00:55.480
Like enhancing intelligence or physical traits like strength, size, etc.
01:01:00.120
Of all of these areas, the one I find most interesting is around mental health.
01:01:06.120
Which is, we understand, for example, autism and schizophrenia have an enormous genetic component.
01:01:13.420
On the surface, it might seem like, hey, wouldn't it be great if fewer people were born with autism and or schizophrenia?
01:01:19.320
But it's really nowhere near that simple, is it?
01:01:21.800
And there's a Pandora's box upon which we have no idea what we could lose as a society
01:01:28.940
if we were to sort of sterilize, quote unquote, some of these conditions.
01:01:34.360
You've obviously touched on this, and I want to come back to mental health.
01:01:37.520
Because in some ways, where we're going to go next in this discussion, I think, is to the last cellular territory, right?
01:01:45.840
To me, that's the most complicated cells of the body, in a sense.
01:01:50.760
And of course, this is one area where it's very difficult to appreciate a phenotype under a microscope or in a scanner.
01:01:59.340
Part of it has to do with the complexity of these genes.
01:02:01.720
But how do you think about what might be inevitably questions that society faces around the use of this type of precision gene editing
01:02:11.940
when it comes to genetic conditions of the brain?
01:02:15.560
Well, the brain is the most complex of all organs, and it's important to understand that complexity.
01:02:22.500
What we know about diseases like autism and schizophrenia is that there are, broadly speaking,
01:02:30.740
two kinds of genes in the entire spectrum of genetics that have to do with mental diseases.
01:02:56.520
Short parents tend to produce shorter children.
01:03:01.740
Now, there are genes in the spectrum of controlling height that are very powerful shove genes.
01:03:18.740
Marfan syndrome is a genetic disorder, a single gene.
01:03:22.600
One gene, if you inherit copies of that gene, you will likely be extremely tall,
01:03:29.760
and you might have other medical and other complications.
01:03:35.260
There's a story that Abraham Lincoln may have inherited, the Marfan gene.
01:03:41.720
Those are relatively rare in the human population of very tall people.
01:03:48.380
The more common variant is what I call nudge genes.
01:03:56.000
Nudge genes move you little by little by little by little by little by little towards increasing height.
01:04:05.880
There may be tens of hundreds of genes that may increase your height little by little by little by little by little
01:04:13.160
until you get 5 feet, 10 inches, 5 feet, 11 inches, 6 feet, et cetera, et cetera.
01:04:19.260
So it's not one gene, but hundreds, if not tens of hundreds.
01:04:29.660
There are certainly genes in the human genome that change your neuron physiology,
01:04:37.000
the physiology of your nerves that are shove genes.
01:04:40.140
In other words, if you inherit them, just like Marfan syndrome, you are likely, much more likely to have mental illness in whatever form it is.
01:04:51.160
They're relatively rare, and they are inherited in families.
01:04:55.540
There's a great book on this written recently about a family that has multiple kids with schizophrenia, et cetera.
01:05:05.200
If I remember correctly, but most mental illness, just by analogy with height, is not the consequence of this shove phenomenon,
01:05:16.540
but are consequences of what I would call death by a thousand cuts, small nudges that would push you towards depression, schizophrenia, autism, et cetera.
01:05:29.140
And in fact, we haven't even found those genes yet, even though we know they exist.
01:05:34.500
In some cases, we haven't even found those genes yet.
01:05:37.440
So the capacity to change those genes is very limited because the examples that I gave you of gene editing, gene alteration technology,
01:05:49.320
are limited to one gene, two genes, three genes.
01:05:53.520
But it's very, very hard to find a way to change those genes, hundreds, potentially tens of hundreds of genes in the mental health spectrum.
01:06:05.240
So it's not as if we can all of a sudden wake up one morning and say,
01:06:10.080
I'm going to change your mental health or change the mental health of your embryo based on the understanding of our shove genes because it just won't happen.
01:06:19.460
So let's now dig into this complexity issue around the brain.
01:06:24.960
I've tried to explain this to people and I've never been able to do a great job of it.
01:06:28.180
You do a great job of it in the book describing the mystery.
01:06:32.620
And you came up with a way to describe it that I thought was fantastic, which was,
01:06:37.120
and I want to make sure I'm getting this right, so correct me if I'm wrong.
01:06:40.620
You said there are two types of problems in science.
01:06:43.180
There are the eye in the sandstorm problems versus the sand in the eye problems.
01:06:51.560
And as the cellular biologists and neurobiologists were getting deeper and deeper into the brain,
01:06:57.640
and it really seemed like they had figured out this thing, these axons, the movement of electricity, these action potentials,
01:07:05.840
they were figuring this out, but they had a little piece of sand in their eye.
01:07:11.660
And then, again, feel free to expand on this if I haven't provided an eloquent enough setup,
01:07:18.480
It's a fanciful description and it's an important distinction and it's a philosophical distinction.
01:07:24.760
The eye in the sandstorm problem is a problem in which you encounter something in medical sciences
01:07:38.200
And I give the example of when we made the transition in physics between Newtonian physics
01:07:44.180
and quantum mechanics and Einsteinian understanding.
01:07:48.920
So, in other words, you reach a place and all of a sudden everything didn't fit.
01:07:53.480
The bending of light, the presence of relativity, etc.
01:07:59.040
So, you needed a completely new theory, a new paradigm, a totally shift in paradigmatic thinking.
01:08:09.380
So, in other words, there's sandstorms everywhere and you can't make sense of the real world.
01:08:14.840
That's one kind of problem and I'm interested in those problems.
01:08:19.800
The sand in the eye problem, as I call it, is a different kind of problem.
01:08:28.500
And it's very important to understand that both of those are really interesting
01:08:32.520
because the sand in the eye problem says that our theory is almost right,
01:08:38.460
but it's not right because there's something, a fact, that won't fit.
01:08:42.860
And the particular example I use is neuronal transmission.
01:08:47.680
So, when people discovered neurons in the brain,
01:08:51.360
they figured out, basically by looking at an anatomy,
01:08:55.240
that neurons in the brain, there was a space between them.
01:09:03.700
If you were an electrician putting out an electrical situation in an apartment,
01:09:09.080
what you wouldn't do is put spaces between the wires
01:09:13.640
so that all of a sudden that space would become a communication between wires.
01:09:20.820
But when people like Ramani Kahal and other scientists figured out how to solve this problem,
01:09:28.620
they understood all of a sudden that nerves have spaces in between them.
01:09:38.840
That is an eye in the sand problem because you say to yourself,
01:09:43.800
wait a second, if the nervous system is just electrical wires strung together,
01:09:49.280
why would you place a space between two electrical wires?
01:09:54.920
And the solution to that problem turns out to be extraordinarily important for neuroscience
01:09:59.860
because what happens between nerves is that an electrical conduction
01:10:11.280
it changes from an electrical conduction to a chemical signal between one nerve to another.
01:10:17.560
And that chemical signal re-sparks an electrical conduction.
01:10:23.500
So you're going chemical, electrical, chemical, electrical, chemical, electrical.
01:10:29.400
And you could say what mad person or what evolutionary process would ever devise a system like this?
01:10:37.020
And the answer is, the reason is very important.
01:10:40.700
Because what your nervous system is doing is in that transmission between electrical, chemical, electrical, chemical,
01:10:48.480
what your nervous system is doing is it's putting weights so that in the chemical transmission,
01:10:59.660
But let's say there are 10 nerves or 10 neurons, nerve cells that are impinging on one nerve cell.
01:11:07.740
So you could assign a weight as to how much this one was transmitting versus another one.
01:11:15.200
And by assigning those weights, by assigning those calibrations,
01:11:29.380
And it's those combinations of inhibition, loudness, etc., etc.,
01:11:35.560
that allow profound things like sentience and conversation and consciousness and so forth.
01:11:45.020
The analogy that's very important is this is exactly or similarly to how neural networks work.
01:11:51.580
There are weights put on how one layer of communication communicates with the second layer of communication.
01:11:59.900
In other words, some are louder than others, some are softer than others.
01:12:09.120
You could say that a very loud signal in that discrimination if the animal happens to bark.
01:12:20.600
A very soft signal could be the weight of the animal.
01:12:27.160
A very loud signal could be the way that the snout of an animal is fixed with the head of the animal.
01:12:44.060
So by adjusting the weights of these combinations, we think by analogy that this is how the brain can discriminate between dogs and cats.
01:12:54.000
We don't know this for sure because this is an area of science that's still in process.
01:13:00.720
But this is a classic example in the 1950s of the idea that why on earth would you take an electrical signal,
01:13:10.560
convert it to a chemical signal, and then convert it back to a micro-signal?
01:13:14.360
The answer is because if it was just an electrical signal, we'd be a box of wires.
01:13:19.220
And a box of wires without the weight between individual signals between the wires is a useless box
01:13:27.620
because we cannot understand how to construct a learning network between a box of wires,
01:13:37.080
whereas we can understand how we can construct a learning network between electrical and chemical stimulation
01:13:45.560
because we can modulate the strength of that chemical stimulation such that we can really actually learn a process.
01:13:54.280
Another way that I like to explain it is using music, which is the electrical signals that travel down the axon are digital.
01:14:03.440
And maybe because I'm an engineer, I do tend to think in terms of digital versus analog processes.
01:14:09.000
But if you explain that digital means it's either completely on or completely off, there is no modulation.
01:14:15.940
And imagine an orchestra that every instrument could only play at one maximum decibel level or not at all.
01:14:29.440
But if now each of those instruments can go up and down and crescendo and decrescendo and modulate,
01:14:36.440
you would now have the analog adjustment of music.
01:14:41.840
That's probably a cruder analogy, but I think it also gets at this point, which is how did evolution figure this out?
01:14:49.480
How much trial and error went into producing something so remarkable, so brilliant.
01:14:57.560
Again, you wouldn't think to engineer this system necessarily.
01:15:01.040
Well, I mean, I think the reason evolution figured it out is, again, learning a purely electrical system,
01:15:08.080
which is sort of like saying you're playing some music, but you don't have any modulation.
01:15:13.140
You're listening to a score, and the score has no modulation.
01:15:17.520
So you play everything at the same volume, at the same tempo, at the same time.
01:15:25.500
What evolution figured out, and by figured out, I don't want to put an anthropomorphic idea on it,
01:15:31.700
but what evolution converged on is the idea that music has tempo, it has pace.
01:15:40.400
Some pieces are softer, some pieces are louder.
01:15:43.140
And by altering this loudness, softness, as we move along in our neurons,
01:15:51.260
that we can produce not just a mechanical output of the score.
01:15:57.360
And your musical analysis is very interesting because that's what we're producing.
01:16:00.860
We're producing not a mechanical output of the score.
01:16:04.980
We're producing a learned output, a mature output of the score.
01:16:11.620
And that mature output has to do very much with modulation.
01:16:24.100
And that is ultimately the music of the cell, but also the music of the brain.
01:16:30.080
So there's many systems we haven't spoken about, but there's one we would be remiss not to speak about
01:16:35.420
because it's near and dear to both of our hearts.
01:16:37.520
So when you went to Oxford to do your PhD as a Rhodes Scholar, you ended up in a lab where you learned immunology,
01:16:45.580
which of course would come to serve you very well as an oncologist and a hematologist today.
01:16:52.860
First is you spoke, of course, of your mentor Enzo in the lab.
01:16:56.840
Help us understand what it is that was bestowed on you from an education perspective, from a learning perspective,
01:17:05.460
as a doctoral student that we don't really get in medical school.
01:17:14.540
But I think anybody who spent time in a lab will understand that there are just certain things that can't be taught in a classroom.
01:17:20.660
You have to learn things by being in a lab if that's the language you want to be able to speak.
01:17:26.220
What are your recollections of that period of time, especially in the beginning when presumably the learning curve was very steep
01:17:31.000
and you're drinking from a fire hose and you don't know much of what's going on,
01:17:34.280
but you've committed to this path of becoming a scientist first, a physician second?
01:17:39.000
It's a very different kind of thinking process.
01:17:44.620
And when I make medicines, I like to make medicines that are important for human life,
01:17:52.740
We've spoken in prior podcasts about some of the new medicines that I've been involved in inventing.
01:17:59.660
Textbook knowledge in medicine is important and biology is important
01:18:04.640
because it lays the groundwork and the foundations of what we know and what we understand.
01:18:13.220
because when you come into the actual laboratory,
01:18:16.880
you understand that there are things that are predictable,
01:18:22.320
And then you get into these eye-in-the-sandstorm and sand-in-the-eye problems,
01:18:31.920
You learn to recognize how to troubleshoot your way out of failure.
01:18:42.940
and try to find me a section on troubleshooting.
01:18:51.280
is the most standard way that we think about medicine and biology.
01:19:14.700
Nothing will tell you about how you select a patient for a clinical trial,
01:19:19.600
how you manage a patient with complications for a clinical trial.
01:19:24.460
There is no information anywhere in that textbook about running that trial.
01:19:31.080
Similarly, run an experiment which will set you up for a clinical trial.
01:19:35.760
There is no information in that textbook about how to troubleshoot,
01:19:40.600
where and how to do that science that allows you to make it into human medicine.
01:19:47.280
What if, for instance, you suddenly find that the medicine that you're working with,
01:19:52.540
you're trying to create, isn't pure, that there's a contamination?
01:20:01.540
And so what you do is you ask your peers who've done this before you,
01:20:17.820
I wanted to write about that process of learning by doing,
01:20:27.020
And that's why that whole chapter exists in the book.
01:20:31.040
There is a kind of learning that we do by doing, that we be by being, that we acquire by acquiring,
01:20:40.980
that cannot be found in any book or textbook in the medical sciences, and there's no way around it.
01:20:49.720
There are a couple of really personal things I want to ask you about, some of them for selfish reasons.
01:20:55.840
For all the times we've had meals together, I don't know how this hasn't occurred to me to ask you,
01:21:00.540
but how and when did this, and when I call it a gift, I don't want to undermine it, Sid,
01:21:07.280
because I don't want to suggest it doesn't require an obscene amount of hard work.
01:21:11.000
But the reality of it is if I spent the rest of my life writing,
01:21:15.060
I would still write like a child compared to an adult in the way that you write.
01:21:19.320
So at what point in your high school, undergraduate, et cetera,
01:21:24.320
did you realize that you had a brilliant way to write?
01:21:28.320
And I will say this, I think you are hands down the best medical writer.
01:21:32.480
I mean, best writer who happens to write about anything that has to do with science and medicine.
01:21:41.060
You know, writing is not an easy process for me,
01:21:52.120
In the next book that I write, maybe this conversation that we're having,
01:21:56.180
or some aspect of this conversation, some question that you ask in this conversation,
01:22:03.480
I have this policy in which there's nothing that's outside my box.
01:22:08.200
It's all part of the box, all part of the whole story.
01:22:12.380
I find that writing is a way for me to think, a way for me to work through my thoughts.
01:22:21.320
And the analogies and the metaphors and the metaphorical parts of my writing
01:22:33.860
They're in service of making me understand why a certain phenomenon is related to another phenomenon.
01:22:45.260
I draw from mythology, from philosophy, from our conversations, from interviews,
01:22:54.300
And in some ways, I feel as if I had to invent that genre, because it was so siloed.
01:23:08.160
There was sharp distinctions between memoir and case histories.
01:23:13.860
There were sharp distinctions between deep history and an interview or journalistic writing.
01:23:20.580
And I said to myself, these distinctions are arbitrary.
01:23:24.320
They only exist to serve a kind of secondary purpose.
01:23:28.540
Why not erase all of them and make a new kind of writing in medicine or in life?
01:23:34.520
Because the most important thing that I think people told me about medical writing was like,
01:23:41.560
when people read writing about medicine, they want to enter your cosmos.
01:23:47.840
They want to know what it's like to be like you.
01:23:55.240
Well, it's like to experience absolutely intense exhilaration when a clinical trial is successful.
01:24:04.480
Absolute depths of depression and crisis when a clinical trial fails.
01:24:10.640
Absolute anticipation, absolute apprehension, absolute admiration for people on whose shoulders
01:24:22.540
And when people said to me, show me your world, I said, okay, I'll show you my world,
01:24:28.340
but I'll show you my world in a way that's like to be like me.
01:24:51.480
At the same time, I want to bring you into that.
01:24:54.060
And that means I will combine memoir, journalistic writing, traveling writing, philosophy, mythology,
01:25:04.120
I'll throw everything in there so that you understand what it's like to be like me.
01:25:09.700
There are two things you talked about in the book, Sid, that were completely unconnected,
01:25:18.760
As you know, Sid, I think a lot about the end of life.
01:25:22.700
I think a lot about how we can delay and push off the end of life.
01:25:28.120
And one of the things that I think a lot about is how quickly life can vanish in a person
01:25:37.100
And these two things that you write about, and again, totally different parts of the book.
01:25:41.240
You talk very openly about your own depression that really kicked in a year after your father's
01:25:48.220
And near the very end of the book, you talk about the end of Virchow's life, which I was not
01:25:54.500
I was completely unaware of that, that he ultimately died as a result of a fall and a broken femur.
01:26:00.000
And within less than six months, he was dead, which is unfortunately far more common than
01:26:07.080
I mean, it is the leading cause of accidental death.
01:26:10.800
And the mortality, as you know, Sid, from a person over the age of 65, if a person at that
01:26:17.480
age or above falls and breaks their femur, depending on the study, it's anywhere from
01:26:24.960
And you do a very good job of explaining the why, because a lot of people, when confronted
01:26:33.740
And I was again confronted by it just two days ago when the swim coach of Stanford, while
01:26:39.440
I was there, of course, I didn't swim at Stanford, but many of my friends did and I knew him and
01:26:46.320
And he fell two weeks ago, broke his hip, and two weeks later, he's dead.
01:26:55.700
It's interesting to me, but what I couldn't believe was how you tied it back to this cell,
01:26:59.940
which was here we have one of these giants of cellular biology who falls and dies, but
01:27:06.540
it's actually the result of a cellular process.
01:27:09.540
It starts with the osteoclast and the osteoblast and the matrix of the hip, and ultimately it leads
01:27:16.920
That's not a leap that I think is easy to make.
01:27:21.420
It's obvious when you think about Burkow's own idea that the body is a citizenship.
01:27:29.540
And the citizenship falls when one part of the citizenship falls.
01:27:37.640
All of a sudden, your Bureau of Transportation decides to take a leave for 20 days.
01:27:54.540
And all of a sudden, people who are dependent on small changes in their lifetimes, wage workers,
01:28:03.540
And then the entire system, the network of systems collapses, all because the Department of Transportation
01:28:14.340
That's the liability, in some ways, of multicellular existence.
01:28:21.120
We talked about multicellular existence as advantages.
01:28:24.660
But there are also liabilities because you depend on your pancreas for insulin.
01:28:31.240
You depend on your brain for sensuous and consciousness.
01:28:36.600
Your brain can't produce movement without muscles.
01:28:38.720
So there's a citizenship that bodies develop and have developed with each other so that
01:28:48.620
And if you take away one piece of that, a broken bone, it pings into a capacity not to
01:28:59.140
Your wasted muscles then communicate with the rest of your body.
01:29:02.580
You and I have talked about hormonal systems before that conduct hormones between wasted
01:29:09.400
And then this pinged system then goes on and on and on until you end up with, as I said.
01:29:17.680
How much did you weigh the pros and cons of writing about such personal matters as your
01:29:27.600
We do still live in a world where it's not entirely clear to me why we view depression
01:29:36.160
For example, if a person says, I have hyperlipidemia and I take 10 milligrams of Lipitor a day, I
01:29:43.760
But if somebody says, I'm really struggling with depression and I take an antidepressant,
01:29:49.200
it just has a different valence to it for some reason.
01:29:55.460
But in the presence of that knowledge, you still chose to talk about this.
01:30:05.860
I talked to my family about it and I made the choice after that conversation.
01:30:11.480
I think that depression can be what's called an organic disorder, a disorder in mood-regulating
01:30:20.220
Just like type 1 diabetes is an organic disorder, a disorder in the inability of pancreatic beta
01:30:29.000
The reason it's different, I think, is that we associate a kind of victimhood to mental disorders.
01:30:42.140
It blames victims for being victims in a way that, you know, you don't say that, oh, you know,
01:30:48.080
you're hypertensive because you have genetics or behaviors, et cetera, et cetera, that are
01:30:57.940
But depression and mental disorders, grief, depression, and perhaps even more complex disorders,
01:31:05.520
schizophrenia, have a sense of blaming the victim.
01:31:09.600
And the victim being the person who's experiencing the disorder.
01:31:14.840
That victimhood, I think, has to do with the idea that the brain is separate from the rest
01:31:25.220
But on the other hand, it's also an organ that has physiology, just like your pancreas
01:31:30.040
has physiology, just like your heart has physiology.
01:31:33.360
And so what I wanted to get away from is this idea of special victimhood and talk about the
01:31:40.840
brain as a cellular cluster, which is in some ways just a cellular cluster like the pancreas
01:31:49.140
or the heart or the liver is a cluster and thereby remove this or defend or even challenge this
01:31:59.660
idea of victimhood and responsibility, because most people who experience severe clinical
01:32:07.580
depression experience it as a consequence of, of course, of environmental and emotional
01:32:14.340
stimulation, the grief of dying, the grief of their situation.
01:32:20.080
But there are neuronal or nervous nerve cells and nerve cell circuits that push them.
01:32:29.660
In biochemical and chemical ways towards the state in which they cannot function.
01:32:36.380
And I want to highlight that that absence of function, if Virka was alive today, Virka would
01:32:43.800
say that absence of function or that dysfunction is not dissimilar to a person who has a failing
01:32:52.200
heart or a failing liver, because that function is a dysfunction of mood regulating circuits and neurons
01:33:02.220
in the brain, just as type 1 diabetes is a dysfunction of insulin regulating cells in the pancreas.
01:33:11.080
And that idea, again, is, I think, very important and I think radical in this book and in all my books.
01:33:21.260
I agree with you completely. I think it is entirely radical and it's, I think, very difficult.
01:33:27.080
You know, I spoke about this with Carl Deseroth. If you haven't read his book, by the way, it's a
01:33:34.140
And Carl was a classmate of mine in medical school and he was equally brilliant then as
01:33:39.360
he is now. But he talks about this idea, right? Which is, it's this entire field of medicine,
01:33:44.500
I'm referring to psychiatry, for which we have not one biomarker, for which we have not one
01:33:50.060
radiographic finding that lends itself to a diagnosis. And so in the example of that failing
01:33:56.200
heart and that failing liver, we have a menu of things to aid in the diagnosis. In fact, it's
01:34:02.300
much easier to make that diagnosis today than when William Osler had to make the diagnosis
01:34:07.860
125 years ago. I mean, today, a medical student can diagnose a failing heart and a failing liver,
01:34:15.280
given enough data. And yet there's still this black box inside of our brains in some ways. And I find it
01:34:23.400
very interesting and I can't help but wonder where we will be in 20 years. Like when I think about
01:34:30.760
oncology today, and I think about what the wish for oncology is in 20 years, and I think about
01:34:36.940
psychiatry today and psychiatry in 20 years, I feel like there's even more potential in psychiatry.
01:34:42.500
And of course, I think the potential in oncology is enormous.
01:34:46.080
I think you've hit the nail on the head, which is to say that biomarkers will help and are always
01:34:51.920
helpful. But ultimately, it's a clinical decision. I always tell people who haven't been in clinical
01:34:59.420
medicine. When you see depression, you know depression. You know that this person has a
01:35:04.960
dysfunction of the neural circuits that regulate mood, just like a patient with type 1 diabetes
01:35:10.880
has a dysfunction in the cells that secret insulin. And even if there are no biomarkers,
01:35:17.020
you know it. This is what humans can see about other humans. There is a disproportionality
01:35:24.040
or a disconnection between the level of grief that a person experiences and the level of grief that
01:35:33.860
persists ennui, the level of psychomotor inability to move that a person experiences when they're
01:35:42.040
clinically depressed. So I think that even in the absence of biomarkers, I think there is a new age
01:35:49.480
that is coming and a respect, I think, for the autonomy of patients who experience neurological
01:35:56.840
and psychiatric diseases. And I think, as you've said before, Deseroth writes about them
01:36:02.060
very carefully and very thoughtfully. There are many people, Andrew Solomon has written about all of
01:36:08.040
this. And I think it's very important because we could find therapies for these. Some of them may be
01:36:13.720
related to things that you and I are very interested in, like alterations in diets, alterations in
01:36:21.080
diets plus medicines, alterations in human physiology that could reset brain circuits,
01:36:28.020
electrical stimulation, as Helen Mayberg and others have been doing. And to treat the problem as if it
01:36:34.940
was just a problem that is sort of a heavy phenomenon is to minimize what the problem is.
01:36:41.920
Sid, there's so much more I wanted to talk with you about, but not surprisingly, we've gone pretty
01:36:47.760
deep in a few things and there are topics like the entire immune system, the epigenetic phenomenon and
01:36:55.760
how we get into cellular reprogramming and Yamanaka factors. I mean, there's, we got through about half
01:37:01.000
of what I wanted to talk about. So I think the only reasonable thing to do here is to say, once the book
01:37:05.500
tour is behind you, once we've both got a little bit more breathing room, we should sit down again and do
01:37:10.920
part three, where we talk about some of these other factors. You have a wonderful way of explaining
01:37:15.800
complicated ideas. And frankly, I think perhaps the single most important thing I wanted to talk
01:37:20.640
about today, which was to bring all of this around the future of science and the culture of anti-science
01:37:27.520
that is propagating. I hesitate to not touch on that now, but I don't think we could do it justice
01:37:32.700
with a glib and short discussion. And I'd, with your blessing, like to postpone that as yet another
01:37:37.280
topic we can explore hopefully in 2023. Would love to. And good luck. I love your podcast and I love being on it.
01:37:45.160
So. Well, thank you, Sid. And congratulations again on another masterpiece. And I'm looking forward to
01:37:50.680
helping to spread the word so that many more people experience the joy of reading the word. Thank you, Sid.
01:37:55.360
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